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Basic Immunology and Early Stage Adjuvant Discovery

Understanding host protective immune responses to pathogens is critical for developing preventive vaccines. NIAID currently supports a wide range of research projects that explore the basic immunology of the innate immune system and its interactions with, and induction of, adaptive immune responses. This work includes studies on the cells and receptors that are targets of adjuvant activity and signaling pathways that modulate adjuvant activity. In addition, many current studies focus on understanding the development of T- and B-cell memory responses. Other recent efforts seek to identify immune correlates of protection that are induced during infection or following successful immunization. Building on this foundation, many of the current adjuvant candidates were identified after basic discoveries in immunology pointed to new receptors, pathways, and cells as possible targets for development of novel adjuvants.

Recent insights into innate immunity also provide a foundation for the development of new vaccine adjuvants that are tailored to stimulate particular immune responses or that might be optimal for particular pathogens. Initial work in adjuvant discovery was focused on compounds that activate various TLRs, and potential adjuvant targets have expanded with new discoveries in innate immunity. Despite an abundance of early stage candidates, only limited attention has been paid to combinations of adjuvants. This will certainly be a fruitful area for future research, because simultaneous targeting of distinct innate immune pathways has the potential to increase vaccine immunogenicity and efficacy while avoiding harmful side effects.

High throughput screening allows researchers to test large molecular libraries for compounds with previously unknown adjuvant activity, or that generate unique responses or signal through specific molecular pathways. Genomic and proteomic approaches have led to deeper insights regarding signaling components of innate immune pathways, which are potential adjuvant targets. These techniques generate large and complex data sets, and sophisticated computational analyses will be required to make optimal use of such information. Eventually, such approaches will provide a more comprehensive view of the affected subcellular signaling pathways and point to targets for further development. Further development includes the application of medicinal chemistry approaches such as structure-activity relationships to rationally modify an adjuvant candidate. Important parameters that can be manipulated by structural modifications include receptor binding specificity and affinity, differential pathway triggering, and reduction of off-target effects. With better ability to manipulate the pathways at the interface of innate and adaptive immunity, researchers will be able to focus on adjuvant targets that stimulate potent responses while minimizing undesirable effects.

Immediate Goals:

Maintain a robust portfolio of basic research on innate immune receptors and their natural ligands in animal and human cells

Identify local innate immune responses to adjuvant:vaccine administration and the optimal routes of administration that lead to durable protection at specific mucosal sites

Discover or engineer adjuvants that potentiate specific types of immune responses; for example, the induction of cellular responses versus the generation of antibodies, or Th1- versus Th2-type immunity

Early in the adjuvant discovery phase, determine how formulation influences adjuvant activity

Study cellular targets of adjuvants in addition to dendritic cells, such as mast cells, NKT cells, and γδT cells

Develop additional systems immunology programs and support focused training programs to optimize the use of genomics, transcriptomics, and bioinformatics to map signaling pathways relevant to adjuvant responses

Promote collaborative multidisciplinary work by teams of immunologists, microbiologists, virologists, mycologists, parasitologists, and vaccine development experts including formulation scientists

Long-Term Goals:

Understand the immunological rules that determine the activities of different classes of adjuvants

Develop a balanced pipeline of adjuvants with the capability to

induce qualitatively distinct types of immune responses for rational design of vaccines against a wide range of pathogens

target immune responses in neonates, the elderly, and immunosuppressed populations

Later Stage Adjuvant Development and Preclinical Testing

Later stage development of candidate adjuvants must proceed through immunological studies, lead compound optimization and formulation, stability testing, pharmacodynamic and pharmacokinetic determinations, and toxicology studies. Preclinical testing and evaluation of adjuvant lead compounds will also include safety studies in appropriate animal models, in vivo localization and clearance studies, dose assessments, and determination of activity via different routes of administration.

In vivo testing of the adjuvant with the vaccine antigen is essential. Species differences in innate immune receptor expression and associated pathways will require the development of strategies to assess in vivo the immunogenicity of adjuvant and antigen combinations. Dose ranging of the adjuvant, the antigen, and combinations of the two, and determining optimal routes of administration in animal models can provide valuable information to begin to estimate appropriate doses, formulations, and routes of administration for human use. Data on the specific immune response, such as gene expression, cytokine or chemokine patterns, correlated with safety and efficacy data, should provide valuable information for predicting immunogenicity in subsequent clinical trials. Thus, the preclinical studies should provide a rational basis for the design of clinical trials using promising adjuvant candidates.

Certain natural products have been identified as adjuvant candidates but are often chemically heterogeneous, and methods for their uniform production and quality control are also needed. In addition, manufacture of vaccines and adjuvants must be done according to the Food and Drug Administration (FDA) current Good Manufacturing Practices (cGMP) to ensure the purity and consistency of product lots. It should be noted that many of these activities are beyond the reach of academic laboratories and small biotechnology companies.

Immediate Goals:

Foster collaborations between basic immunologists, adjuvant researchers, and formulation experts to determine the effects of formulation on the immunogenicity, efficacy, and safety of adjuvanted vaccines

Assess the potential of combinations of adjuvants for particular vaccines and define methods to analyze mechanisms of action different from those conferred by each adjuvant alone

Explore the usefulness of various adjuvants in enhancing the efficacy of vaccines delivered in heterologous prime-boost immunization regimens

Promote collaborations among investigators to test adjuvant candidates with multiple vaccine antigens in a variety of experimental systems

Support a centralized repository to distribute experimental adjuvants, model antigens (vaccines), and/or formulated standardized vaccines to the research community to test in different vaccine systems, while preserving intellectual property rights of the developer

Clinical Assessment of Adjuvants

The NIAID Division of Intramural Research (DIR), Division of Acquired Immunodeficiency Syndrome (DAIDS), Vaccine Research Center (VRC), and Division of Microbiology and Infectious Diseases (DMID) all support clinical trials to improve current vaccines and to develop new vaccines for infectious diseases. DAIDS and DMID have established clinical trial networks that could implement future studies on adjuvants for HIV-1 vaccines or vaccines against opportunistic infections, as well as other infectious diseases. DAIT supports targeted research programs that study the responses to infection or vaccination of special populations, such as the elderly, young children, and immunocompromised individuals. The purpose of these programs is to identify human immune response parameters and defects that differ from the effective responses to infection and vaccination seen in healthy adults. In addition, genomic profiling and the discovery of human SNPs that might help predict the outcome of vaccination or infection are being studied in different populations.

NIAID supports clinical trials for the development of vaccines against specific pathogens and some of these trials include adjuvants as vaccine components. NIAID has worked closely with colleagues in academia, industry, and FDA to support trials that are well planned and efficiently executed. NIAID will build on past experience in this area to help ensure the successful design, implementation, and completion of future trials to evaluate novel adjuvanted vaccines and develop robust adjuvant:vaccine formulations appropriate for use even in resource-poor areas.

NIAID has a long and fruitful record of collaboration with industry and private foundations in carrying out vaccine clinical trials, which will continue to be of great value in studies to assess new adjuvants.

Immediate Goals:

Collaborate with industry sponsors in Phase I clinical trials of promising adjuvanted vaccine candidates to assess toxicity and reactogenicity using 1:1 randomization

Use correlates of immunogenicity obtained from clinical trials to develop in vitro assays to predict toxicity and reactogenicity of future adjuvant:vaccine combinations

Develop novel assays to assess mucosal protection in humans

Establish biomarkers for safety and efficacy and test their predictive value

Work with the Centers for Disease Control and Prevention, FDA, and industry to design appropriate clinical studies to generate and evaluate data for long-term safety evaluation

Work with the Biological Advanced Research and Development Authority and other government agencies to support the development of non-commercial but necessary adjuvanted vaccines through Phase III clinical trials